Is ERCC3 p.Trp374Ter (c.1115_1120dup) pathogenic?

ERCC3 p.Trp374Ter (c.11151120dup) is classified Pathogenic/Likely pathogenic in ERCC3 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-03-17). Ultra-rare (popmax 0.0118%, nfe); Associated with ERCC3-related disorder.

What condition is associated with ERCC3 p.Trp374Ter (c.1115_1120dup)?

ERCC3 p.Trp374Ter (c.1115_1120dup) is associated with ERCC3-related disorder, xeroderma pigmentosum group B, trichothiodystrophy 2, photosensitive (ClinVar).

How common is ERCC3 p.Trp374Ter (c.1115_1120dup) in the general population?

ERCC3 p.Trp374Ter (c.1115_1120dup) is ultra-rare (popmax 0.0118%, nfe) (gnomAD).

ERCC3 p.Trp374Ter

c.1115_1120dup · rs778865255 · VCV1335950

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0118%, nfe)

Conditions

ERCC3-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 8 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0118% European (non-Finnish) · 139/1,180,044 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00956%

Overall 0.00898% 145/1,614,090 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0118%	8,490
Admixed American	0.00667%	15,001
Remaining individualsnot grpmax-eligible	0.0032%	31,243

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ERCC3
Protein: p.Trp374Ter
Coding: c.1115_1120dup
MANE Select: NM_000122
dbSNP: rs778865255
Type: Duplication
Location: chr2:127286924 (GRCh38)
Gene constraint: LOEUF 0.797 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.34 · 56 PDB
Residue 374: the helicase atp-binding domain; an α-helix

Full ERCC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ERCC3-related disorder

Also linked: xeroderma pigmentosum group B trichothiodystrophy 2, photosensitive xeroderma pigmentosum

Similar variants

ERCC3 p.Asp474fs Pathogenic/Likely pathogenic ★★ same condition
ERCC3 p.Asp81fs Likely pathogenic ★ same condition
ERCC3 p.Glu588fs Conflicting classifications of pathogenicity ★ same condition
ERCC3 c.1828-1G>C Likely pathogenic ★★ same condition
ERCC3 c.471+1G>A Pathogenic ★★ same condition
ERCC3 c.657+1G>A Likely pathogenic ★★ same condition
ERCC3 p.Arg109Ter Pathogenic/Likely pathogenic ★★ same condition
ERCC3 p.Arg195Ter Pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ercc3-p-trp374ter (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown